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[PMID]:28826029
[Au] Autor:Masondo NA; Kulkarni MG; Finnie JF; Van Staden J
[Ad] Endereço:Research Centre for Plant Growth and Development, School of Life Sciences, University of KwaZulu-Natal, Pietermaritzburg Campus, Private Bag X01, Scottsville 3209, South Africa.
[Ti] Título:Influence of biostimulants-seed-priming on Ceratotheca triloba germination and seedling growth under low temperatures, low osmotic potential and salinity stress.
[So] Source:Ecotoxicol Environ Saf;147:43-48, 2018 Jan.
[Is] ISSN:1090-2414
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Extreme temperatures, drought and salinity stress adversely affect seed germination and seedling growth in crop species. Seed priming has been recognized as an indispensable technique in the production of stress-tolerant plants. Seed priming increases seed water content, improves protein synthesis using mRNA and DNA and repair mitochondria in seeds prior to germination. The current study aimed to determine the role of biostimulants-seed-priming during germination and seedling growth of Ceratotheca triloba (Bernh.) Hook.f. (an indigenous African leafy vegetable) under low temperature, low osmotic potential and salinity stress conditions. Ceratotheca triloba seeds were primed with biostimulants [smoke-water (SW), synthesized smoke-compound karrikinolide (KAR ), Kelpak (commercial seaweed extract), phloroglucinol (PG) and distilled water (control)] for 48h at 25°C. Thereafter, primed seeds were germinated at low temperatures, low osmotic potential and high NaCl concentrations. Low temperature (10°C) completely inhibited seed germination. However, temperature shift to 15°C improved germination. Smoke-water and KAR enhanced seed germination with SW improving seedling growth under different stress conditions. Furthermore, priming seeds with Kelpak stimulated percentage germination, while PG and the control treatment improved seedling growth at different PEG and NaCl concentrations. Generally, high concentrations of PEG and NaCl brought about detrimental effects on seed germination and seedling growth. Findings from this study show the potential role of seed priming with biostimulants in the alleviation of abiotic stress conditions during seed germination and seedling growth in C. triloba plants.
[Mh] Termos MeSH primário: Furanos/farmacologia
Germinação/efeitos dos fármacos
Pedaliaceae/efeitos dos fármacos
Piranos/farmacologia
Plântulas/efeitos dos fármacos
Sementes/efeitos dos fármacos
Estresse Fisiológico/efeitos dos fármacos
[Mh] Termos MeSH secundário: Temperatura Baixa
Secas
Osmose
Pedaliaceae/crescimento & desenvolvimento
Salinidade
Plântulas/crescimento & desenvolvimento
África do Sul
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Furans); 0 (Pyrans); 0 (karrikinolide)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE


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[PMID]:29196265
[Au] Autor:Inoue Y; Moriwaki K; Ueda Y; Takeuchi T; Higuchi K; Asahi M
[Ad] Endereço:Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan.
[Ti] Título:Elevated O-GlcNAcylation stabilizes FOXM1 by its reduced degradation through GSK-3ß inactivation in a human gastric carcinoma cell line, MKN45 cells.
[So] Source:Biochem Biophys Res Commun;495(2):1681-1687, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors. Given that FOXM1 expression was reported to be elevated in gastric cancer, we examined the effect of high glucose or an inhibitor of O-GlcNAc hydrolase, Thiamet G (TMG), on FOXM1 protein expression in a human gastric cancer cell line, MKN45 cells, and confirmed that FOXM1 protein level and the cell proliferation were upregulated. To investigate the molecular mechanisms by which FOXM1 protein expression is regulated by O-GlcNAcylation, the effect of high glucose and TMG on FOXM1 ubiquitination was examined in MKN45 cells. As a result, the ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3ß. High glucose and TMG treatment increased phospho-serine 9 GSK-3ß, an inactive form, and the degradation of FOXM1 protein was suppressed by treatment of GSK-3ß inhibitors in MKN45 cells. Taken together, we suggest that high glucose and elevated O-GlcNAcylation stabilize FOXM1 protein by its reduced degradation via GSK-3ß inactivation in MKN45 cells, suggesting that the higher risk of gastric cancer in diabetic patients could be partially due to O-GlcNAcylation-mediated FOXM1 stabilization.
[Mh] Termos MeSH primário: Proteína Forkhead Box M1/metabolismo
Glicogênio Sintase Quinase 3 beta/metabolismo
Neoplasias Gástricas/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/metabolismo
Acilação
Linhagem Celular Tumoral
Proliferação Celular
Complicações do Diabetes/etiologia
Complicações do Diabetes/metabolismo
Complicações do Diabetes/patologia
Inibidores Enzimáticos/farmacologia
Proteína Forkhead Box M1/química
Glucose/metabolismo
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores
Glicogênio Sintase Quinase 3 beta/química
Seres Humanos
Processamento de Proteína Pós-Traducional
Estabilidade Proteica/efeitos dos fármacos
Proteólise/efeitos dos fármacos
Piranos/farmacologia
Neoplasias Gástricas/etiologia
Neoplasias Gástricas/patologia
Tiazóis/farmacologia
Ubiquitinação/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
beta-N-Acetil-Hexosaminidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (FOXM1 protein, human); 0 (Forkhead Box Protein M1); 0 (Pyrans); 0 (Thiazoles); 0 (thiamet G); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); IY9XDZ35W2 (Glucose); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE


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[PMID]:28452143
[Au] Autor:Jain MR; Joharapurkar AA; Kshirsagar SG; Patel VJ; Bahekar RH; Patel HV; Jadav PA; Patel PR; Desai RC
[Ad] Endereço:Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
[Ti] Título:ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus.
[So] Source:Br J Pharmacol;174(14):2346-2357, 2017 Jul.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Dipeptidyl peptidase (DPP)-4 inhibitors increase levels of glucagon-like peptide-1 (GLP-1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP-4 inhibitor, ZY15557, that has a sustained action and long half-life. EXPERIMENTAL APPROACH: We studied the potency, selectivity, efficacy and duration of action of ZY15557, in vitro, with assays of DPP-4 activity. In vivo, the pharmacodymamics and pharmacokinetics of ZY15557 were studied, using db/db mice and Zucker fatty rats, along with normal mice, rats, dogs and non-human primates. KEY RESULTS: ZY15557 is a potent, competitive and long acting inhibitor of DPP-4 (K 5.53 nM; K 3.2 × 10 ·s , half-life 35.8 min). ZY15557 treatment inhibited DPP-4 activity, and enhanced active GLP-1 and insulin in mice and rats, providing dose-dependent anti-hyperglycaemic effects. Anti-hyperglycaemic effects were also observed in db/db mice and Zucker fatty rats. Following oral dosing, ZY15557 significantly inhibited plasma DPP-4 activity, determined ex vivo, in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicts a half-life for ZY15557 in humans of up to 60 h. CONCLUSIONS AND IMPLICATIONS: ZY15557 is a potent, competitive and long acting DPP-4 inhibitor. ZY15557 showed similar DPP-4 inhibition across different species. ZY15557 showed excellent oral bioavailability in preclinical species. It showed a low plasma clearance (CL) and large volume of distribution (V ) across species, resulting in an extended half-life.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Tipo 2/tratamento farmacológico
Dipeptidil Peptidase 4/metabolismo
Inibidores da Dipeptidil Peptidase IV/farmacologia
Piranos/farmacologia
[Mh] Termos MeSH secundário: Animais
Diabetes Mellitus Experimental/metabolismo
Diabetes Mellitus Tipo 2/metabolismo
Inibidores da Dipeptidil Peptidase IV/química
Cães
Relação Dose-Resposta a Droga
Seres Humanos
Macaca mulatta
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Obesos
Estrutura Molecular
Piranos/química
Ratos
Ratos Sprague-Dawley
Ratos Wistar
Ratos Zucker
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Pyrans); 0 (ZY15557); EC 3.4.14.5 (Dipeptidyl Peptidase 4)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13842


  4 / 5446 MEDLINE  
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[PMID]:29331652
[Au] Autor:Gao X; Zheng Y; Ruan X; Ji H; Peng L; Guo D; Jiang S
[Ad] Endereço:Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China.
[Ti] Título:Salinomycin induces primary chicken cardiomyocytes death via mitochondria mediated apoptosis.
[So] Source:Chem Biol Interact;282:45-54, 2018 Feb 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Salinomycin, as a polyether ionophore antibiotic, is extensively used as a feed additive against coccidiosis in poultry and as a growth promoter of ruminants worldwide. Owing to its narrow therapeutic index, numerous intoxication have been reported in target/non-target animals by overdosage, misuse or drug interactions as well as human who consumed salinomycin accidently. Salinomycin-induced cardiotoxicity in chicken and non-target animals is considered as a major contributor to animal death. In the current study, we aim to elucidate the underlying mechanism of its myocardial toxicity using primary chicken myocardial cell as an in vitro model. The results showed that salinomycin altered cellular morphology and induced cell death in a concentration-dependent manner. Salinomycin treatment elevated the permeability of the cell membrane and leaded to the efflux of enzymes, including creatine kinase (CK) and lactate dehydrogenase (LDH). Flow cytometry analysis indicated the number of apoptotic cells increased significantly by salinomycin exposure. Furthermore, caspase-3 and caspase-9 were activated at gene and protein level rather than caspase-8, along with the up-regulation of apoptosis genes Bax, Cytochrome C, Apoptotic peptidase activating factor 1 (Apaf-1) and the down-regulation of Bcl-2. Salinomycin-induced mitochondrial dysfunction was accompanied by the significant decrease of mitochondrial membrane potential (MMP) and the severe ultrastructure damage. In conclusion, these findings suggest that the toxic dose of salinomycin induces severe cardiomyocytes death through mitochondria mediated apoptosis pathway.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Morte Celular/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Miócitos Cardíacos/efeitos dos fármacos
Piranos/farmacologia
[Mh] Termos MeSH secundário: Animais
Proteínas Reguladoras de Apoptose/metabolismo
Células Cultivadas
Galinhas
Regulação para Baixo/efeitos dos fármacos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias/metabolismo
Miócitos Cardíacos/metabolismo
Transdução de Sinais/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoptosis Regulatory Proteins); 0 (Pyrans); 62UXS86T64 (salinomycin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180115
[St] Status:MEDLINE


  5 / 5446 MEDLINE  
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[PMID]:29337674
[Au] Autor:Zhou JB; Sun YY; Zheng YL; Yu CQ; Lin HQ; Pang JY
[Ad] Endereço:1School of Chemistry Sun Yat-Sen University, Guangzhou 510275, P. R. China.
[Ti] Título:A study on blocking store-operated Ca2+ entry in pulmonary arterial smooth muscle cells with xyloketals from marine fungi.
[So] Source:Acta Pharm;67(4):557-567, 2017 Dec 20.
[Is] ISSN:1846-9558
[Cp] País de publicação:Croatia
[La] Idioma:eng
[Ab] Resumo:In this study, the effect of four xyloketals 1-4 on store-operated calcium entry (SOCE) was investigated in primary distal pulmonary arterial smooth muscle cells (PASMCs) isolated from mice. The results showed that xyloketal A (1), an unusual ketal with C-3 symmetry, exhibited strong SOCE blocking activity. Secretion of interleukin-8 (IL-8) was also inhibited by xyloketal A. The parallel artificial membrane permeability assay (PAMPA) of 1-4 suggested that these xyloketals penetrated easily through the cell membrane. Moreover, the molecular docking study of xyloketal A with activation region of the stromal interaction molecule (STIM) 1 and the calcium release-activated calcium modulator (ORAI) 1 (STIM1-ORAI1) protein complex, the key domain of SOCE, revealed that xyloketal A exhibited a noncovalent interaction with the key residue lysine 363 (LYS363) in the identified cytosolic regions in STIM1-C. These findings provided useful information about xyloketal A as a SOCE inhibitor for further evaluation.
[Mh] Termos MeSH primário: Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores
Músculo Liso Vascular/efeitos dos fármacos
Artéria Pulmonar/efeitos dos fármacos
Piranos/farmacologia
Xylariales/química
[Mh] Termos MeSH secundário: Animais
Cálcio/análise
Permeabilidade da Membrana Celular/efeitos dos fármacos
Interleucina-8/análise
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Simulação de Acoplamento Molecular
Músculo Liso Vascular/química
Músculo Liso Vascular/citologia
Artéria Pulmonar/química
Artéria Pulmonar/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Release Activated Calcium Channels); 0 (Interleukin-8); 0 (Pyrans); 0 (xyloketal A); 0 (xyloketal B); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:28455615
[Au] Autor:Meng S; Wu H; Wang L; Zhang B; Bai L
[Ad] Endereço:State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
[Ti] Título:Enhancement of antibiotic productions by engineered nitrate utilization in actinomycetes.
[So] Source:Appl Microbiol Biotechnol;101(13):5341-5352, 2017 Jul.
[Is] ISSN:1432-0614
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Nitrate is necessary for primary and secondary metabolism of actinomycetes and stimulates the production of a few antibiotics, such as lincomycin and rifamycin. However, the mechanism of this nitrate-stimulating effect was not fully understood. Two putative ABC-type nitrate transporters were identified in Streptomyces lincolnensis NRRL2936 and verified to be involved in lincomycin biosynthesis. With nitrate supplementation, the transcription of nitrogen assimilation genes, nitrate-specific ABC1 transporter genes, and lincomycin exporter gene lmrA was found to be enhanced and positively regulated by the global regulator GlnR, whose expression was also improved. Moreover, heterologous expression of ABC2 transporter genes in Streptomyces coelicolor M145 resulted in an increased actinorhodin production. Further incorporation of a nitrite-specific transporter gene nirC, as in nirC-ABC2 cassette, led to an even higher actinorhodin production. Similarly, the titers of salinomycin, ansamitocin, lincomycin, and geldanamycin were increased with the integration of this cassette to Streptomyces albus BK3-25, Actinosynnema pretiosum ATCC31280, S. lincolnensis LC-G, and Streptomyces hygroscopicus XM201, respectively. Our work expanded the nitrate-stimulating effect to many antibiotic producers by utilizing the nirC-ABC2 cassette for enhanced nitrate utilization, which could become a general tool for titer increase of antibiotics in actinomycetes.
[Mh] Termos MeSH primário: Actinobacteria/genética
Antibacterianos/biossíntese
Lincomicina/biossíntese
Nitratos/metabolismo
Streptomyces/genética
[Mh] Termos MeSH secundário: Actinobacteria/metabolismo
Proteínas de Transporte de Ânions/genética
Antraquinonas/metabolismo
Antibacterianos/metabolismo
Proteínas de Bactérias/genética
Regulação Bacteriana da Expressão Gênica
Nitrogênio/metabolismo
Piranos/metabolismo
Streptomyces/metabolismo
Streptomyces coelicolor/genética
Transativadores/genética
Transativadores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anion Transport Proteins); 0 (Anthraquinones); 0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (GlnR protein, Streptomyces coelicolor); 0 (NirC protein, Bacteria); 0 (Nitrates); 0 (Pyrans); 0 (Trans-Activators); 62UXS86T64 (salinomycin); BOD072YW0F (Lincomycin); G4HH387T6Z (actinorhodin); N762921K75 (Nitrogen)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1007/s00253-017-8292-7


  7 / 5446 MEDLINE  
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[PMID]:29202406
[Au] Autor:Zang Y; Song X; Li C; Ma J; Chu S; Liu D; Ren Q; Li Y; Chen N; Zhang D
[Ad] Endereço:State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
[Ti] Título:Pyrano[3,2-a]carbazole alkaloids as effective agents against ischemic stroke in vitro and in vivo.
[So] Source:Eur J Med Chem;143:438-448, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of pyrano[3,2-a]carbazole alkaloids were designed and synthesized as analogues of Claulansine F (Clau F, 10a) isolated from Clausena lansium. Some of compounds showed strong neuroprotective effects and were promising agents against ischemic stroke. Among these compounds, 7c was the most active in inhibiting the programmed death of PC12 cells and primary cortical neurons. This compound induced neuroprotection following ischemic reperfusion and decreased neurological deficit scores in treated animals. Furthermore, 7c could penetrate the blood-brain barrier (BBB) in rats, and its exposure in the brain was 4.3-fold higher than that in plasma. More importantly, compared to edaravone, 7c exhibited stronger free radical scavenging activity. Our findings suggest that 7c may be promising for further evaluation as an intervention for ischemic stroke.
[Mh] Termos MeSH primário: Alcaloides/farmacologia
Isquemia Encefálica/tratamento farmacológico
Carbazóis/farmacologia
Fármacos Neuroprotetores/farmacologia
Piranos/farmacologia
Acidente Vascular Cerebral/tratamento farmacológico
[Mh] Termos MeSH secundário: Alcaloides/síntese química
Alcaloides/química
Animais
Barreira Hematoencefálica/efeitos dos fármacos
Isquemia Encefálica/patologia
Carbazóis/síntese química
Carbazóis/química
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Relação Dose-Resposta a Droga
Peróxido de Hidrogênio/farmacologia
Masculino
Estrutura Molecular
Neurônios/efeitos dos fármacos
Fármacos Neuroprotetores/síntese química
Fármacos Neuroprotetores/química
Células PC12
Piranos/síntese química
Piranos/química
Ratos
Ratos Sprague-Dawley
Acidente Vascular Cerebral/patologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6-tert-butyl-3',3',3-trimethylpyrano(3,2-a)carbazole); 0 (Alkaloids); 0 (Carbazoles); 0 (Neuroprotective Agents); 0 (Pyrans); BBX060AN9V (Hydrogen Peroxide)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


  8 / 5446 MEDLINE  
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[PMID]:28454878
[Au] Autor:Tung CL; Chen JC; Wu CH; Peng YS; Chen WC; Zheng HY; Jian YJ; Wei CL; Cheng YT; Lin YW
[Ad] Endereço:Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
[Ti] Título:Salinomycin acts through reducing AKT-dependent thymidylate synthase expression to enhance erlotinib-induced cytotoxicity in human lung cancer cells.
[So] Source:Exp Cell Res;357(1):59-66, 2017 08 01.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Erlotinib (Tarceva ) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in the treatment of human non-small cell lung cancer (NSCLC). Salinomycin, a polyether antibiotic, has been promising a novel therapeutic agent for lung cancer, and down-regulated the expression of thymidylate synthase (TS) in NSCLC cell lines. Previous study showed that against EGFR and TS was strongly synergistic cytotoxicity in NSCLC cells. In this study, we showed that erlotinib (1.25-10µM) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung squamous cell carcinoma H1703 and adenocarcinoma H1975 cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting AKT activity with PI3K inhibitor LY294002 enhanced the cytotoxicity and cell growth inhibition of erlotinib. A combination of erlotinib and salinomycin resulted in synergistic enhancement of cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced protein levels of phospho-AKT(Ser473), phospho-AKT(Thr308), and TS. Overexpression of a constitutive active AKT (AKT-CA) or Flag-TS expression vector reversed the salinomycin and erlotinib-induced synergistic cytotoxicity. Our findings suggested that the down-regulation of AKT-mediated TS expression by salinomycin enhanced the erlotinib-induced cytotoxicity in NSCLC cells. These results may provide a rationale to combine salinomycin with erlotinib for lung cancer treatment.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carcinoma Pulmonar de Células não Pequenas/enzimologia
Cloridrato de Erlotinib/farmacologia
Neoplasias Pulmonares/enzimologia
Proteínas Proto-Oncogênicas c-akt/metabolismo
Piranos/farmacologia
Timidilato Sintase/metabolismo
[Mh] Termos MeSH secundário: Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Linhagem Celular Tumoral
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/patologia
Receptor do Fator de Crescimento Epidérmico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Pyrans); 62UXS86T64 (salinomycin); DA87705X9K (Erlotinib Hydrochloride); EC 2.1.1.45 (Thymidylate Synthase); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171209
[Lr] Data última revisão:
171209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:29107028
[Au] Autor:Pelin M; Kilcoyne J; Nulty C; Crain S; Hess P; Tubaro A; Sosa S
[Ad] Endereço:Department of Life Sciences, University of Trieste, Via A. Valerio 6, 34127 Trieste, Italy.
[Ti] Título:Toxic equivalency factors (TEFs) after acute oral exposure of azaspiracid 1, -2 and -3 in mice.
[So] Source:Toxicol Lett;282:136-146, 2018 Jan 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Azaspiracids (AZAs) are marine algal toxins that can be accumulated by edible shellfish to cause a foodborne gastrointestinal poisoning in humans. In the European Union, only AZA1, -2 and -3 are currently regulated and their concentration in shellfish is determined through their toxic equivalency factors (TEFs) derived from the intraperitoneal lethal potency in mice. Nevertheless, considering the potential human exposure by oral route, AZAs TEFs should be calculated by comparative oral toxicity data. Thus, the acute oral toxicity of AZA1, -2 and -3 was investigated in female CD-1 mice treated with different doses (AZA1: 135-1100µg/kg; AZA2 and AZA3: 300-1100µg/kg) and sacrificed after 24h or 14days. TEFs derived from the median lethal doses (LD ) were 1.0, 0.7 and 0.5, respectively for AZA1, -2 and -3. In fact, after 24h from gavage administration, LD were 443µg/kg (AZA1; 95% CL: 350-561µg/kg), 626µg/kg (AZA2; 95% CL: 430-911µg/kg) and 875µg/kg (AZA3; 95% CL: 757-1010µg/kg). Mice dead more than 5h after the treatment or those sacrificed after 24h (doses: ≥175µg AZA1/kg, ≥500µg AZA2/kg and ≥600µg AZA3/kg) showed enlarged pale liver, while increased serum markers of liver alteration were recorded even at the lowest doses. Blood chemistry revealed significantly increased serum levels of K ions (≥500mg/kg), whereas light microscopy showed tissue changes in the gastrointestinal tract, liver and spleen. No lethality, macroscopic, tissue or haematological changes were recorded two weeks post exposure, indicating reversible toxic effects. LC-MS/MS analysis of the main organs showed a dose-dependency in gastrointestinal absorption of these toxins: at 24h, the highest levels were detected in the stomach and, in descending order, in the intestinal content, liver, small intestine, kidneys, lungs, large intestine, heart as well as detectable traces in the brain. After 14days, AZA1 and AZA2 were still detectable in almost all the organs and intestinal content.
[Mh] Termos MeSH primário: Furanos/toxicidade
Toxinas Marinhas/toxicidade
Piranos/toxicidade
Compostos de Espiro/toxicidade
[Mh] Termos MeSH secundário: Administração Oral
Animais
Relação Dose-Resposta a Droga
Feminino
Furanos/farmacocinética
Dose Letal Mediana
Toxinas Marinhas/farmacocinética
Camundongos Endogâmicos
Mytilus edulis/química
Especificidade de Órgãos
Piranos/farmacocinética
Compostos de Espiro/farmacocinética
Distribuição Tecidual
Testes de Toxicidade Aguda
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Furans); 0 (Marine Toxins); 0 (Pyrans); 0 (Spiro Compounds); 0 (azaspiracid); 0 (azaspiracid-2); 0 (azaspiracid-3)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171201
[Lr] Data última revisão:
171201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171107
[St] Status:MEDLINE


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[PMID]:29087802
[Au] Autor:Halay E; Ay E; Salva E; Ay K; Karayildirim T
[Ad] Endereço:a Scientific Analysis Technological Application and Research Center , Usak University , Usak , Turkey.
[Ti] Título:Syntheses of 1,2,3-triazole-bridged pyranose sugars with purine and pyrimidine nucleobases and evaluation of their anticancer potential.
[So] Source:Nucleosides Nucleotides Nucleic Acids;36(9):598-619, 2017 Sep 02.
[Is] ISSN:1532-2335
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:With the aim to create a library of compounds with potential bioactivities by combining special characteristics of two important groups such as nucleobases and carbohydrates, twenty 1,4-disubstituted-triazole nucleosides were synthesized in good yields (80-94%) using the copper catalyzed 'Click' reaction between azido-modified pento- or hexopyranoses and alkyne-bearing pyrimidine or purine nucleobases. Structural elucidation was made with the assistance of spectroscopic techniques such as FTIR, 1D-, 2D-NMR, and ESI-TOFMS. All the synthesized triazole nucleosides were evaluated for their cytotoxic activity against three human cancer cell lines (MDA-MB-231, Hep3B, PC-3) by using the MTT assay. Particularly, compounds 3a and 1b were identified as potential hits against Hep3B cell.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Nucleosídeos de Purina/química
Piranos/química
Nucleosídeos de Pirimidina/química
Triazóis/síntese química
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/química
Linhagem Celular Tumoral
Técnicas de Química Sintética
Seres Humanos
Triazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Purine Nucleosides); 0 (Pyrans); 0 (Pyrimidine Nucleosides); 0 (Triazoles)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171101
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2017.1346258



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